Muscle wasting is common in advanced chronic kidney disease (CKD) and adversely affects morbidity and mortality. In 2/3 of males with advanced CKD, serum testosterone (TT) levels are reduced and likely contribute to the wasting. As TT in relatively safe physiologic replacement doses, increases muscle mass in otherwise normal TT deficient subjects, we hypothesize that physiologic TT replacement will be effective in preventing and treating the loss of muscle mass and function in CKD patients, will improve quality of life and may reduce some cardiovascular disease (CVD) risk factors. The mechanisms whereby TT affect its response in uremic muscle is poorly understood; we postulate that skeletal muscle benefit occurs through androgen receptor upregulation, changes in the balance between IGF-1 and myostatin, changes in the ubiquitin-proteasome and calpain proteolytic systems, and suppression of inflammatory cytokines. Our specific aims are: 1. To determine whether physiologic TT replacement is effective in improving muscle mass, strength and quality of life in males with low serum TT levels and advanced CKD. 2. To elucidate the mechanisms whereby TT stimulates muscle hypertrophy in CKD. 3. To determine whether TT can improve some CVD risk factors in CKD. Males 55-75 years of age with advanced stable or slowly progressive CKD (GFR 15-29 ml/min/ 1.73m2) and low serum TT levels (<300 ng/ml) will be studied. Subjects (18/group) will be a treated with placebo or TT in physiologic replacement doses and studied over 16 weeks with monitoring for any side effects. Healthy sedentary men, with normal TT levels, will serve as normal baseline controls and will not be treated. The following will be measured before and after treatment; Lean body and fat mass by DEXA, thigh muscle volume and composition by MRI, muscle strength and function quality of life, lipids, inflammatory markers and insulin sensitivity. Vastus lateralis muscle biopsies will be taken at baseline and post-treatment and examined for fiber type, cross-sectional area, myonuclei and satellite cell number, mRNA and protein expression of key positive and negative regulators of muscle mass (IGF-1, myostatin and their receptors, androgen receptors, selected inflammatory cytokines) and key components of the ubiquitin-proteasome and calpain proteolytic systems. This study tests whether physiologic TT replacement therapy is effective in preventing and treating loss of muscle mass and function in CKD and whether it also improves quality of life and reduces some CVD risk factors. Furthermore the study should provide new insight into the molecular mechanisms of muscle wasting in uremia. If effective as anticipated, this TT replacement strategy will form the basis for more extensive studies of TT therapy. This could be combined with exercise or another anabolic agent and extended to include females and younger subjects with CKD. Muscle wasting is common in advanced chronic kidney disease (CKD) and adversely affects morbidity and mortality. This is true also for other disease such as lung and heart disease. In 2/3 of males with advanced CKD serum testosterone levels are reduced, and likely contributes to the wasting. We plan to test whether normalizing the low testosterone levels will be effective in preventing and treating the loss of muscle mass and function in CKD patients and improving quality of life. If effective in these patients, then this holds the potential of improving management of patients, not only with CKD, but also those with other muscle wasting illnesses. [unreadable] [unreadable] [unreadable]